A randomized controlled study to evaluate the effect of bexarotene on amyloid-β and apolipoprotein E metabolism in healthy subjects
| Autor: | Philip B. Verghese, Tim West, Joel B. Braunstein, David M. Holtzman, Gary E. Landreth, Timothy Veenstra, Kaushik Ghosal, Randall J. Bateman, Michael Haag |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apolipoprotein E medicine.medical_specialty Amyloid β Retinoid X receptor Central nervous system β amyloid Pharmacology law.invention 03 medical and health sciences 0302 clinical medicine Randomized controlled trial law Internal medicine Genotype medicine Bexarotene Chemistry Healthy subjects Metabolism Featured Article Alzheimer's disease Psychiatry and Mental health 030104 developmental biology Endocrinology medicine.anatomical_structure lipids (amino acids peptides and proteins) Neurology (clinical) 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Alzheimer's & Dementia : Translational Research & Clinical Interventions |
| ISSN: | 2352-8737 |
| DOI: | 10.1016/j.trci.2016.06.001 |
| Popis: | Introduction We conducted a phase Ib proof of mechanism trial to determine whether bexarotene (Targretin) increases central nervous system (CNS) apolipoprotein E (apoE) levels and alters Aβ metabolism in normal healthy individuals with the APOE ε3/ε3 genotype. Methods We used stable isotope labeling kinetics (SILK-ApoE and SILK-Aβ) to measure the effect of bexarotene on the turnover rate of apoE and Aβ peptides and stable isotope spike absolute quantitation (SISAQ) to quantitate their concentrations in the cerebrospinal fluid (CSF). Normal subjects were treated for 3 days with bexarotene (n = 3 women, 3 men, average 32 years old) or placebo (n = 6 women, average 30.2 years old) before administration of C13-leucine and collection of plasma and CSF over the next 48 hours. Bexarotene concentrations in plasma and CSF were also measured. Results Oral administration of bexarotene resulted in plasma levels of 1 to 2 μM; however, only low nM levels were found in CSF. Bexarotene increased CSF apoE by 25% but had no effect on metabolism of Aβ peptides. Discussion Bexarotene has poor CNS penetration in normal human subjects. Drug treatment resulted in a modest increase in CSF apoE levels. The absence of an effect on Aβ metabolism is likely reflective of the low CNS levels of bexarotene achieved. This study documents the utility of SILK-ApoE technology in measuring apoE kinetics in humans. Trial Registration This trial is registered at clinicaltrials.gov (NCT02061878). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text